Dynamics of Platelet Counts in Major Trauma: The Impact of Haemostatic Resuscitation and Effects of Platelet Transfusion-A Sub-Study of the Randomized Controlled RETIC Trial.
ABSTRACT: Although platelets play a central role in haemostasis, the dynamics of platelet counts during haemostatic resuscitation, the response to platelet transfusion, and effects on clinical outcome are poorly described for trauma patients. As a sub-study of the already published randomized controlled RETIC Study "Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma" trial, we here analysed whether the type of first-line haemostatic resuscitation influences the frequency of platelet transfusion and determined the effects of platelet transfusion in coagulopathic patients with major trauma. Patients randomly received first-line plasma (FFP) or coagulation factor concentrates (CFC), mainly fibrinogen concentrate. In both groups, platelets were transfused to maintain platelet counts between 50 and 100 × 109 /L. Transfusion rates were significantly higher in the FFP (n = 44) vs. CFC (n = 50) group (FFP 47.7% vs. CFC 26%); p = 0.0335. Logistic regression analysis adjusted for the stratification variables injury severity score (ISS) and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion (odds ratio (OR) 5.79 (1.89 to 20.62), p = 0.0036) and this effect was larger than a 16-point increase in ISS (OR 4.33 (2.17 to 9.74), p =0.0001). In conclusion, early fibrinogen supplementation exerted a platelet-saving effect while platelet transfusions did not substantially improve platelet count and might contribute to poor clinical outcome.
Project description:This study investigated the effect of a high ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) within the first 6 and 24 ?h after admission on mortality in patients with severe, blunt trauma.This retrospective observational study included 189 blunt trauma patients with an Injury Severity Score (ISS) ?16 requiring RBC transfusions within the first 24? h. Receiver operating characteristic (ROC) curve analysis was performed to calculate cut-off values of the FFP/RBC ratio for outcome. The patients were then divided into two groups according to the cut-off value. Patient survival was compared between groups using propensity score matching (PSM).The area under the ROC curve was 0.57, and the FFP/RBC ratio was 1.0 at maximum sensitivity (0.57) and specificity (0.67). All patients were then divided into two groups (FFP/RBC ratio ?1 or <1) and analyzed using PSM and inverse probability of treatment weighting (IPTW). The unadjusted hazard ratio (HR) was 0.44, and the adjusted HR was 0.29. The HR was 0.38 by PSM and 0.41 by IPTW. The survival rate was significantly higher in patients with an FFP/RBC ratio ?1 within the first 6? h.Severe blunt trauma patients transfused with an FFP/RBC ratio ?1 within the first 6? h had an HR of about 0.4. The transfusion of an FFP/RBC ratio ?1 within the first 6? h was associated with the outcomes of blunt trauma patients with ISS ?16 who need a transfusion within 24? h.
Project description:Hemostatic resuscitation has been shown to be beneficial for patients with trauma, but there is little evidence that it is equally beneficial for bleeding patients without trauma. The practice of a high transfusion ratio of fresh frozen plasma (FFP) to red blood cells (RBCs) has spread to other surgical and medical fields.To identify whether ratio-based resuscitation in patients without trauma is associated with improved survival.This study is a retrospective review of all massive transfusions provided in an urban academic hospital from January 1, 2009, through December 31, 2012. Massive transfusion was defined as the transfusion of at least 10 U of RBCs in the first 24 hours after a patient's admission to the operating room, emergency department, or intensive care unit. All patients who received massive transfusions within the study period and survived more than 30 minutes after hospital arrival were counted (n=865). Patients were grouped into those with trauma and those without trauma. Sources of data included the Research Patient Data Registry, patients' medical records, and blood bank records. All data collection occurred between April 26, 2013, and April 26, 2015. Data analysis took place from April 27, 2015, and June 22, 2016.Examination of FFP:RBC transfusion ratios for patients without trauma.There were 865 massive transfusion events that occurred within 4 years, transfusing 16?569 U of RBCs, 13?933 U of FFP, 5228 U of cryoprecipitate, and 22?635 U of platelets. Most of these transfusions were received by patients without trauma (767 [88.7%]), by men (582 [67.3%]), and for intraoperative bleeding (544 [62.9%]). The FFP:RBC ratios of survivors and nonsurvivors were nearly identical: the ratio for survivors was 1:1.5 (interquartile range [IQR], 1:1.1-1:2.2) and for nonsurvivors was 1:1.4 (IQR, 1:1.1-1:1.9; P?=?.43). Among the 767 patients without trauma, there was no difference in the adjusted odds ratio (aOR) for 30-day mortality when comparing the high FFP:RBC ratio vs the low FFP:RBC ratio subgroups (aOR, 1.10; 95% CI, 0.72-1.70; P?=?.65). In vascular surgery, the aOR for death favored the high FFP:RBC ratio subgroup (aOR,?0.16; 95% CI, 0.03-0.79; P?=?.02). However, in general surgery and medicine, the aOR for death favored the low FFP:RBC ratio subgroup; general surgery: aOR, 4.27 (95% CI, 1.28-14.22; P?=?.02); medicine: aOR, 8.48 (95% CI, 1.50-47.75; P?=?.02).High FFP:RBC transfusion ratios are applied mostly to patients without trauma, who account for nearly 90% of all massive transfusion events. Thirty-day survival was not significantly different in patients who received a high FFP:RBC ratio compared with those who received a low ratio.
Project description:PBMC were exposed to Cell Free Nucleic Acids (CFNA) extracted from blood products eligible for transfusion: Red Blood Cell units (RBC), Fresh Frozen Plasma units (FFP). PBMC alone exposed to the same extract from PBS were used as a control (PBMC+control). PBMC alone were also used as control. The used positive control was PBMC exposed to Lipopolysaccharide (LPS) Overall design: exposition of PBMC to CFNA, RNA extarction and gene expression array (24h) PFC = FFP = Fresh Frozen Plasma units CE = RBC = Red Blood Cell units CP = PC = Platelet Concentrates
Project description:Haemorrhage remains a leading cause of morbidity and mortality in trauma patients. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated with bleeding, transfusion and outcome. Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines for the treatment of trauma patients, but evidence is lacking regarding the treatment safety and efficacy. We aim to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation.This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded, investigator-initiated phase II trial. The trial population consists of 40 adult patients (>18 years) with traumatic, critical bleeding admitted to the Level 1 Trauma Centre at Rigshospitalet in Copenhagen, with immediate need for blood transfusion on arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Patients will receive either pre-emptive administration of a bolus dose of 60-70 mg/kg fibrinogen concentrate (Riastap®) or placebo 0.9 % saline in equal volume to active treatment, both given as intravenous infusion blinded for the person administering the infusion. The primary end point is the change in thrombelastograph (TEG®) functional fibrinogen maximum amplitude in millimetres at 15 min after the intervention. The follow-up period on safety events and mortality will be until day 30. To detect a difference in the change from baseline to the 15-minute post-randomization measurement of 6-8 mm in TEG® functional fibrinogen maximum amplitude with a power of 0.90 and alpha of 0.05, we require 19 patients in each group. We have chosen to include 40 patients, 20 evaluable patients in each randomization group in case of attrition, in the present trial.Patients considered to be included in the trial will temporarily have a compromised consciousness because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next of kin and the patients' general practitioner or the patients will co-sign as soon as possible. This trial will test whether immediate pre-emptive fibrinogen concentrate administered to adult trauma patients as first-line treatment of trauma haemorrhage will increase the clot strength as evaluated by thrombelastography, transfusion requirements and survival in patients receiving haemostatic resuscitation according to current standard of care.EudraCT no. 2014-003978-16 (22/1 2015); ClinicalTrials.gov: NCT02344069 . Registered on 14 January 2015. Trial protocol version 4.2 (23-12-2014).
Project description:BACKGROUND: Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. METHODS: The inflammatory response from pre-activated (endotoxin-stimulated) and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC), platelet concentrates (PC) and fresh frozen plasma (FFP) was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. RESULTS: Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product-induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. CONCLUSION: Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells.
Project description:Macrophages were exposed to CFNA from different blood products prior to gene expression array: Red Blood Cells units (RBC), Fresh Frozen Plasma Units (FFP) and Platelet Concentrates (PC). Extracts from PBS were used as controls. Biological triplicates were included with three different macrophage cell lines (M1, M2, M3). Overall design: CFNA extraction, exposition to human macrophages, RNA extraction after 24h, gene expression array PFC = FFP = Fresh Frozen Plasma units CE = RBC = Red Blood Cell units CP = PC = Platelet Concentrates
Project description:BACKGROUND:Acute respiratory distress syndrome (ARDS) following trauma is historically associated with crystalloid and blood product exposure. Advances in resuscitation have occurred over the last decade, but their impact on ARDS is unknown. We sought to investigate predictors of postinjury ARDS in the era of hemostatic resuscitation. METHODS:Data were prospectively collected from arrival to 28 days for 914 highest-level trauma activations who required intubation and survived more than 6 hours from 2005 to 2016 at a Level I trauma center. Patients with ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 mmHg or less during the first 8 days were identified. Two blinded expert clinicians adjudicated all chest radiographs for bilateral infiltrates in the first 8 days. Those with left-sided heart failure detected were excluded. Multivariate logistic regression was used to define predictors of ARDS. RESULTS:Of the 914 intubated patients, 63% had a ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 or less, and 22% developed ARDS; among the ARDS cases, 57% were diagnosed early (in the first 24 hours), and 43% later. Patients with ARDS diagnosed later were more severely injured (ISS 32 vs. 20, p = 0.001), with higher rates of blunt injury (84% vs. 72%, p = 0.008), chest injury (58% vs. 36%, p < 0.001), and traumatic brain injury (72% vs. 48%, p < 0.001) compared with the no ARDS group. In multivariate analysis, head/chest Abbreviated Injury Score scores, crystalloid from 0 to 6 hours, and platelet transfusion from 0 to 6 hours and 7 to 24 hours were independent predictors of ARDS developing after 24 hours. CONCLUSIONS:Blood and plasma transfusion were not independently associated with ARDS. However, platelet transfusion was a significant independent risk factor. The role of platelets warrants further investigation but may be mechanistically explained by lung injury models of pulmonary platelet sequestration with peripheral thrombocytopenia. LEVEL OF EVIDENCE:Prognostic study, level IV.
Project description:Administration of fibrinogen concentrate, targeting improved maximum clot firmness (MCF) of the thromboelastometric fibrin-based clot quality test (FIBTEM) is effective as first-line haemostatic therapy in aortic surgery. We performed a post-hoc analysis of data from a randomised, placebo-controlled trial of fibrinogen concentrate, to investigate whether fibrinogen concentrate reduced transfusion requirements for patients with platelet counts over or under 100×10(9)/L.Aortic surgery patients with coagulopathic bleeding after cardiopulmonary bypass were randomised to receive either fibrinogen concentrate (n=29) or placebo (n=32). Platelet count was measured upon removal of the aortic clamp, and coagulation and haematology parameters were measured peri-operatively. Transfusion of allogeneic blood components was recorded and compared between groups.After cardiopulmonary bypass, haemostatic and coagulation parameters worsened in all groups; plasma fibrinogen level (determined by the Clauss method) decreased by 43-58%, platelet count by 53-64%, FIBTEM maximum clot firmness (MCF) by 38-49%, FIBTEM maximum clot elasticity (MCE) by 43-54%, extrinsically activated test (EXTEM) MCF by 11-22%, EXTEM MCE by 25-41% and the platelet component of the clot by 23-39%. Treatment with fibrinogen concentrate (mean dose 7-9 g in the 4 groups) significantly reduced post-operative allogeneic blood component transfusion requirements when compared to placebo both for patients with a platelet count?100×10(9)/L and for patients with a platelet count<100×10(9)/L.FIBTEM-guided administration of fibrinogen concentrate reduced transfusion requirements when used as a first-line haemostatic therapy during aortic surgery in patients with platelet counts over or under 100×10(9)/L.
Project description:BACKGROUND:Up to 40% of combat casualties with a truncal injury die of massive hemorrhage before reaching a surgeon. This hemorrhage can be prevented with damage control resuscitation (DCR) methods, which are focused on replacing shed whole blood by empirically transfusing blood components in a 1:1:1:1 ratio of platelets:fresh frozen plasma:erythrocytes:cryoprecipitate (PLT:FFP:RBC:CRYO). Measurement of hemostatic function with rotational thromboelastometry (ROTEM) may allow optimization of the type and quantity of blood products transfused. Our hypothesis was that incorporating ROTEM measurements into DCR methods at the US Role 3 hospital at Bagram Airfield, Afghanistan would change the standard transfusion ratios of 1:1:1:1 to a product mix tailored specifically for the combat causality. METHODS:This retrospective study collected data from the Department of Defense Trauma Registry to compare transfusion practices and outcomes before and after ROTEM deployment to Bagram Airfield. Over the course of six months, 134 trauma patients received a transfusion (pre-ROTEM) and 85 received a transfusion and underwent ROTEM testing (post-ROTEM). Trauma teams received instruction on ROTEM use and interpretation, with no provision of a specific transfusion protocol, to supplement their clinical judgment and practice. RESULTS:The pre and post groups were not significantly different in terms of mortality, massive transfusion protocol activation, mean injury severity score, or coagulation measurements. Despite the difference in size, each group received an equal total number of transfusions. However, the post-ROTEM group received a significant increase in PLT and CRYO transfusions ratios, 4× and 2×, respectively. CONCLUSION:The introduction of ROTEM significantly improved adherence to DCR practices. The transfusion differences suggest that aggressive DCR without thromboelastometry data may result in reduced hemostatic support and underestimate the need for PLT and CRYO. Thus, future controlled trials should include ROTEM-guided coagulation management in trauma resuscitation. LEVEL OF EVIDENCE:Therapeutic, level IV.
Project description:Importance:Optimal transfusion management is crucial when treating patients with trauma. However, the association of an early, high transfusion ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBC) with survival remains uncertain. Objective:To study the association of an early, high FFP-to-PRBC ratio with all-cause 30-day mortality in patients with severe bleeding after trauma. Design, Setting, and Participants:This cohort study analyzes the data included in a multicenter national French trauma registry, Traumabase, from January 2012 to July 2017. Traumabase is a prospective, active, multicenter adult trauma registry that includes all consecutive patients with trauma treated at 15 trauma centers in France. Overall, 897 patients with severe bleeding after trauma were identified using the following criteria: (1) received 4 or more units of PRBC during the first 6 hours or (2) died from hemorrhagic shock before receiving 4 units of PRBC. Exposures:Eligible patients were divided into a high-ratio group, defined as an FFP-to-PRBC ratio more than 1:1.5, and a low-ratio group, defined as an FFP-to-PRBC ratio of 1:1.5 or less. The ratio was calculated using the cumulative units of FFP and PRBC received during the first 6 hours of management. Main Outcomes and Measures:A Cox regression model was used to analyze 30-day survival with the transfusion ratio as a time-dependent variable to account for survivorship bias. Results:Of the 12 217 patients included in the registry, 897 (7.3%) were analyzed (median [interquartile range] age, 38 (29-54) years; 639 [71.2%] men). The median (interquartile range) injury severity score was 34 (22-48), and the overall 30-day mortality rate was 33.6% (301 patients). A total of 506 patients (56.4%) underwent transfusion with a high ratio and 391 (43.6%) with a low ratio. A high transfusion ratio was associated with a significant reduction in 30-day mortality (hazard ratio, 0.74; 95% CI, 0.58-0.94; P = .01). When only analyzing patients who had complete data, a high transfusion ratio continued to be associated with a reduction in 30-day mortality (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04). Conclusions and Relevance:In this analysis of the Traumabase registry, an early FFP-to-PRBC ratio of more than 1:1.5 was associated with increased 30-day survival among patients with severe bleeding after trauma. This result supports the use of early, high FFP-to-PRBC transfusion ratios in patients with severe trauma.